Highlights from Recent Cancer Literature
Journal: Cancer Research (2017)

High-grade glioma (HGG) is the leading cause of cancer-related death in children. Mackay and colleagues assembled data from 1,067 pediatric HGG for integrated genomic, epigenomic, and transcriptomic analysis. Cases with H3.3G34R/V- or H3K27M-mutant histone genes were uniformly fatal, while significant numbers survived in the histone wild-type group. The Heidelberg DNA methylation classifier identified five groups, specifically H3.3G34R/V, H3K27M, H3 wild-type, low- grade glioma-like, and pleomorphic xanthoastrocytoma-like, with BRAFV600E mutations. Not surprisingly, long-term survivors clustered with the low-grade gliomas. Re-analysis of DNA copy number and somatic variants identified several novel recurrent events and assigned driver events to the majority of cases. This study highlights the power of pooling smaller published cohorts, identifying clinically meaningful groups and new driver alterations, which could aid in both preclinical modeling and clinical risk stratification.Mackay A, Burford A, Carvalho D, Izquierdo E, Fazal-Salom J, Taylor KR, et al. Integrated molecular meta-analysis of 1,000 pediatric high-grade and diffuse intrinsic pontine glioma. Cancer Cell 2017;32:520–37.e5.Colon cancer is driven by deregulation of the Wnt/β-catenin signaling pathway. Huang and colleagues show that the damage-specific DNA-binding protein DDB2 is important for β-catenin–mediated activation of RNF43, an E3 ligase that restricts Wnt signaling by removing Wnt receptors from the cell surface. Human hyperplastic colonic foci showed reduced expression of DDB2 and RNF43, with DDB2 required for expression of RNF43. EZH1 and β-catenin were recruited by DDB2 to the Rnf43 gene, enabling interaction with distant TCF4/β-catenin binding sites in the intron of Rnf43. DDB2 is thus required for RNF43 to function as a negative feedback regulator of Wnt signaling. Transgenic mice genetically deficient in DDB2 had increased susceptibility to developing colon tumors. Thus, the authors identified a novel function of DDB2 as a partner and regulator of Wnt signaling, with relevance in colon cancer development.Huang S, Fantini D, Merrill B, Bagchi S, Guzman G, Raychaudhuri P. DDB2 is a novel regulator of Wnt-signaling in colon cancer. Cancer Research; Published OnlineFirst October 11, 2017; doi: 10.1158/0008-5472.CAN-17-1570.Details of how BRCA1 interacts with BRCA1-associated RING domain protein 1 (BARD1) to regulate repair of DNA double-stranded breaks by homologous recombination (HR) have been lacking, primarily due to difficulties of obtaining full-length protein for functional studies. Zhao and colleagues developed methods to purify high-quality, full-length BRCA1 in complex with BARD1. BRCA1-BARD1 interacted physically with the RAD51 recombinase to enhance recombination. Through biochemistry and single-molecule imaging, BRCA1–BARD1 promoted RAD51-mediated DNA strand invasion during HR repair, a step in which the RAD51–ssDNA (single-stranded DNA) filament invades the template double-stranded DNA. Interestingly, the cancer-associated BARD1K140N mutation impaired interactions between BRCA1-BARD1 and RAD51, compromising RAD51-mediated DNA strand invasion. These findings clarify functions of BRCA1-BARD1 in late steps of HR repair and subsequent tumor suppression.Zhao W, Steinfeld JB, Liang F, Chen X, Maranon DG, Jian Ma C, et al. BRCA1-BARD1 promotes RAD51-mediated homologous DNA pairing. Nature; Published online October 4, 2017; doi: 10.1038/nature24060.Senescent cells facilitate changes within the microenvironment by secreting a variety of inflammatory factors, collectively referred to as the senescence-associated secretory phenotype (SASP). Mechanisms regulating the SASP are not fully understood. Gluck and colleagues demonstrate localization of the DNA-dependent pattern recognition receptor cGAS to nuclear blebs (cytosolic chromatin fragments) in senescent cells with decreased expression of the nuclear envelope protein lamin B1. Canonical activation of the innate DNA-sensing pathway cGAS-STING triggered the production of type I interferons and other inflammatory cytokines, some of which overlapped with the SASP. The cGAS-STING pathway was also required for in vivo senescence induction by radiation and oncogene activation. These data suggest that senescence stressors induce loss of nuclear envelope integrity, providing access to DNA for cGAS-STING activation, resulting in paracrine type I interferon signaling, induction of senescence, and subsequent production of SASP.Glück S, Guey B, Gulen MF, Wolter K, Kang TW, Schmacke NA, et al. Innate immune sensing of cytosolic chromatin fragments through cGAS promotes senescence. Nat Cell Biol 2017;19:1061–70.Cancer cells that develop resistance to a specific drug may become addicted to its continued presence. Kong and colleagues examine melanoma cells resistant to BRAF inhibition (BRAFi), which die rapidly once the BRAFi is withdrawn. Using a CRISPR-Cas9–mediated screen for cells capable of surviving BRAFi withdrawal, they identified mutations in ERK2 and in genes encoding the downstream transcription factors JUNB and FRA1. Comparing transcriptomes of BRAFi-resistant melanoma cells with those in which the BRAFi was withdrawn revealed transcriptional reprogramming consistent with the phenotypic switch commonly observed in epithelial-mesenchymal transition. Significantly, alternating BRAFi withdrawal from such drug-resistant cancer cells with treatment of noncytotoxic doses of a chemotherapeutic resulted in a dramatic increase in cell death, providing a route to translating these findings into the clinic.Kong X, Kuilman T, Shahrabi A, Boshuizen J, Kemper K, Song JY, et al. Cancer drug addiction is relayed by an ERK2-dependent phenotype switch. Nature 2017;550:270–4.Braun and colleagues used an in vivo shRNA screen to show that the arginine methyl-transferase PRMT5 is a pivotal regulator of glioblastoma. The clinically relevant small-molecule PRMT5 inhibitor (EPZ015666) could reduce proliferation and prolong survival of glioblastoma mouse models. Bioinformatic analyses of EPZ015666-sensitive and -resistant cell lines implicated RNA splicing and spliceosome activity as key targets. Specifically, loss of PRMT5 activity resulted in a reduced subset of polyadenylated RNA containing a nonspliced intron, a detained intron, while exhibiting little effect on generalized RNA splicing. Incompletely spliced pre-mRNA were retained in the nucleus and not translated until some regulatory signal induced the splicing of the remaining intron. Thus, PRMT5 overexpression results in enhanced splicing of numerous detained intron–containing RNAs that drive proliferation, and therapeutic targeting of this mechanism might benefit glioblastoma patients.Braun CJ, Stanciu M, Boutz PL, Patterson JC, Calligaris D, Hiquchi F, et al. Coordinated splicing of regulatory detained introns within oncogenic transcripts creates an exploitable vulnerability in malignant glioma. Cancer Cell 2017;32:411–426.e11.Note: Breaking Advances are written by Cancer Research editors. Readers are encouraged to consult the articles referred to in each item for full details on the findings described.